ATM mediates oxidative stress-induced dephosphorylation of DNA ligase IIIα

Among the three mammalian genes encoding DNA ligases, only the LIG3 gene does not have a homolog in lower eukaryotes. In somatic mammalian cells, the nuclear form of DNA ligase III alpha forms a stable complex with the DNA repair protein XRCC1 that is also found only in higher eukaryotes. Recent studies have shown that XRCC1 participates in S phase-specific DNA repair pathways independently of DNA ligase III alpha and is constitutively phosphorylated by casein kinase II. In this study we demonstrate that DNA ligase III alpha, unlike XRCC1, is phosphorylated in a cell cycle-dependent manner. Specifically, DNA ligase III alpha is phosphorylated on Ser123 by the cell division cycle kinase Cdk2 beginning early in S phase and continuing into M phase. Interestingly, treatment of S phase cells with agents that cause oxygen free radicals induces the dephosphorylation of DNA ligase III alpha. This oxidative stress-induced dephosphorylation of DNA ligase III alpha is dependent upon the ATM (ataxia-telangiectasia mutated) kinase and appears to involve inhibition of Cdk2 and probably activation of a phosphatase.